In focus: peanut allergy

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New allergy triggers, such as peanuts are becoming relevant. Recent research confirms that early tolerance formation can significantly reduce the risk of peanut contact. On the other hand, studies show that supplementation with human milk oligosaccharides (HMO) may reduce the risk of cow's milk allergy. Even for therapy, such supplementation with HMO is promising. In this publication you will get update on current state of allergy research.

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New allergy triggers, such as peanuts are becoming relevant. Recent research confirms that early tolerance formation can significantly reduce the risk of peanut contact. On the other hand, studies show that supplementation with human milk oligosaccharides (HMO) may reduce the risk of cow's milk allergy. Even for therapy, such supplementation with HMO is promising. In this publication you will get update on current state of allergy research.

oligosaccharides (HMO) may reduce the risk of cow's milk allergy. Even for therapy, such supplementation with HMO is promising. On the following pages, we would therefore like to inform you about the current state of allergy research, which is also of interest for daily practice.

In trend: allergies and anaphylaxis

More than 17 million people in Europe suffer from food allergies, and one in four school-age children suffers from an allergic condition - with an upward trend. In addition, the number of severe and potentially life-threatening allergic reactions, due to food allergies, is also increasing in children.

Some people's immune systems mistakenly react to allergens with exaggerated reactions. This leads to an overproduction of IgE antibodies. The timing of the introduction of foods consumed in early childhood seems to play an important role. In addition, the amount of stomach acid and the composition of bacteria in the gut can influence susceptibility to food allergies.

It is known that babies with food allergies are more likely to develop other allergic diseases such as asthma later in life. One explanation is that food allergies and other allergic diseases probably have many risk factors in common. Diseases that may co-occur with food allergies are asthma, allergic rhinitis and eczema.
Anaphylaxis is an increasing paediatric clinical emergency that is difficult to diagnose. A generally accepted definition is also still missing. A common definition of anaphylaxis is "a severe allergic reaction that is rapid in onset and can lead to death".

The most common causes of anaphylaxis are food, drugs and insect stings (bees, wasps). The reaction may begin minutes after exposure and may progress rapidly, leading to constriction of the airways, skin and intestinal symptoms and altered heart rhythm. In severe cases, it can lead to complete airway obstruction, shock and death.

Anaphylaxis can affect several body systems at the same time. The skin is involved in 80% of anaphylactic incidents: in the form of itching, rash and general redness or swelling below the skin surface (angioedema). In other cases, the respiratory tract may be involved with irritation and inflammation in the nose (acute rhinitis) or asthma. The digestive tract (nausea, vomiting, stomach cramps or diarrhoea) or the cardiovascular system (with palpitations, increased heart rate or low blood pressure) may be affected. This can lead to dizziness, unconsciousness and, in the worst case, respiratory or cardiac arrest.

Europe-wide evidence-based guidelines for health professionals and better training on the diagnosis of food allergies could improve the current situation. Setting clear guidelines for food labelling according to allergens would also reduce the risk for food allergy sufferers.

Europãische Akademie fur Allergie und klinische Immunologie (EAACI): Lebensmit- telallergie & Anaphylaxie Offentliche Erklãrung, o.J.

Food allergies at a glance

•    More than 17 million people in Europe suffer from food allergies. Of these, 3.5 million are younger than 25.
•    The greatest increase is in children and adolescents, especially in the number of life-threatening allergic reactions.
•    Across Europe, food allergy is the most common cause of anaphylaxis in children aged 0-14 years.
•    Research suggests that the number of hospital admissions for severe allergic reactions in children in Europe has increased 7-fold in the last 10 years.
•    Anaphylaxis as such is not considered common,
but the incidence may be underestimated. In addition, the effects of a life-threatening anaphylactic reaction are significant.
•    Most people who report suffering from some form of food allergy self-diagnose and use treatment strategies that are not monitored by a doctor.
•    More than 120 foods are described as triggers of food allergies.
•    However, the foods that most often cause severe allergic reactions are milk, eggs, peanuts, tree nuts, (stone) fruits and some vegetables. Allergies to fish and shellfish are less common, but usually severe.
•    In continental Europe, the most common food allergies in children are to eggs, cow's milk and peanuts, and in adults to fresh fruit, peanuts, tree nuts and vegetables.
•    However, there are national differences: In the UK, for example, walnuts, hazelnuts and peanuts pose the greatest threat, causing 50% of all life-threatening allergic reactions. In Scandinavia and northern Europe, on the other hand, shellfish and cod are frequent triggers.

European Academy of Allergy and Clinical immunology (EAACI): Food Allergy & Anaphylaxis Public Declaration, o.J.

Not “peanuts”

Between 0.5 and 1 per cent of children in Germany suffer from a peanut allergy. It can be assumed that this number will increase in the coming years, similar to the situation in the USA and Great Britain. 

Peanuts are one of the most common and strongest triggers of severe allergic reactions. Allergy to peanuts is a serious condition that can even be fatal. Contact with the smallest amounts is often enough to trigger a violent reaction. This is not limited to oral intake, by the way. Even a handshake with an acquaintance who has previously eaten peanuts can be enough.

Unlike many other food allergens, a peanut allergy usually lasts a lifetime. There is a strict ban on contact to avoid reactions. But the avoidance strategy is not so easy to sustain. Research shows that 60 per cent of children come into unintentional contact with peanuts over a five-year period, as the allergy-causing peanut protein is not only found in flips, peanut butter or Asian dishes. It can also be present in sweets, bakery products and ready meals, transmitted for example by production and packaging equipment.

Satisfaction with oraI immunotherapy

Peanut allergic participants in two studies reported satisfaction with use, efficacy and overall satisfaction with active treatment after 1,1.5 and 2 years of daily therapy.

The efficacy and safety of defatted powder of Arachis hypogaea L, seed (peanut), a biological medicine approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for oral peanut immunotherapy, was studied in peanut allergic patients in the phase 3 PALISADE study and an open-label follow-up study (ARC 004). Participant satisfaction with treatment was assessed as an exploratory endpoint after approximately 1,1.5 and 2 years of therapy.

The treatment satisfaction questionnaire was completed by participants at the PALISADE and ARC004 final visits. Participants aged > 12 years answered the questionnaire forthemselves; for participants < 12 years, they had their caregivers answer vicariously.

Participants consistently indicated that they were satisfied with all efficacy and convenience items (scores > 4) and very satisfied with the drug's ability to treat the condition (scores > 6).
The mean scores of the 5-point scales showed that participants were convinced that the drug was a good treatment option and that the positive aspects of the treatment outweighed the negative ones (scores > 4).

PALISADE: oral immuno-therapy for peanut allergy 

The PALISADE (Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization) study is a multicentre, double-blind, placebo- controlled phase 3 study conducted at 66 sites in 10 countries in North America and Europe. The efficacy and safety of AR101 were tested in children and adults with peanut allergy.

AR101 is a new peanut-derived oral biologic medication that has a daily peanut protein maintenance dose of 300 mg of peanut protein with a distinctive protein profile.

The PALISADE study included 555 participants with confirmed peanut allergy aged 4 to 55 years, focusing on those aged 4 to 17 years (N=496). The primary efficacy endpoint was the proportion of participants in this group who were able to take a provocative dose of 600 mg or more without dose-limiting symptoms.

250 of 372 participants (67.2 %) who received active oral treatment were able to absorb a dose of 600 mg or more of peanut protein without dose-limiting symptoms, compared with 5 of 124 participants (4.0 %) who received placebo.
During the Exit Food Challenge, the maximum severity of symptoms was 25% of participants in the AR101 group and 59 % of participants in the placebo group (moderate to severe in 5 % and 11 %, respectively). Overall, 34.7 % of participants in the drug group had mild adverse events (AEs), compared with 50.0% of participants in the placebo group; 59.7 %, or 44.4 %, of participants had adverse events (AEs) classified as moderate; and 4.3 %, or 0.8 %, had adverse events (AEs) classified as severe. Efficacy was not demonstrated in participants 18 years or older.
In this phase 3 study, treatment with AR101 resulted in higher doses of peanut protein that could be taken without dose-limiting symptoms and a lower severity of symptoms during peanut exposure.

Vickery BP et al.: NEJM 2018 - DOI: 10.1056/NEJMoal812856 

First peanut allergy treatment available in the EU 

Peanut allergy is one of the most common food allergies in Europe. From 2005 to 2015, their prevalence among children doubled. In addition, there were seven times more hospital admissions due to severe allergic reactions.

The European Commission (EC) has now granted a marketing authorisation for PALFORZIA [defatted powder of Arachis hypogaea L, seeds (peanuts)] for the treatment of peanut allergy. Palforzia is indicated for the treatment of patients aged 4 to 17 years with a confirmed diagnosis of peanut allergy. Use may be continued in patients 18 years and olderand must be in conjunction with a peanut-free diet.

The approval means that for the first time there is an approved treatment option for peanut allergy in the EU.

Palforzia is a complex biological medicine and is administered according to a set dosing schedule - an approach that builds on many years of research into oral immunotherapy (OIT). In OIT, the specific allergenic proteins are first taken in very small amounts and then gradually increased. Over time, this can lead to allergic reactions to the allergen being attenuated. The pharmaceutical-grade preparation ensures a consistent allergen profile for precise dosing from 0.5 mg (equivalent to 1/600 of a peanut) to 300 mg.

Palforzia is not indicated for the treatment of allergic symptoms and does not provide immediate relief for such symptoms. For this reason, the medicinal product must not be used for the emergency treatment of allergic reactions, including anaphylaxis. The patient must be able to access adrenaline for self-injection at any time. 

Efficiency and safety of oral immunotherapy

The aim of a multicentre study was to investigate the efficacy of an orally administered biological drug (AR101) in peanut-allergic children.

The European ARTEMIS study was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial conducted in 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden and the UK. The study enrolled children and adolescents with peanut allergy aged 4 to 17 years who developed dose-limiting symptoms to 300 mg or less of peanut protein (equivalent to approximately one peanut kernel) in a double-blind, placebo-controlled food provocation test at baseline.

Participants were randomly assigned (3:1) to either a daily dose of AR101 oral immunotherapy (AR101 group) or placebo (placebo group). All participants, investigators and caregivers were anonymised regarding treatment assignment until the end of the study.

The dose was increased every 2 weeks over a period of 6 months until a dose of 300 mg was reached, which was maintained for 3 months. The primary endpoint was the proportion of participants in the intention -to-treat or safety population - defined as participants who had received at least one dose of the assigned drug - who could consume a single dose of 1,000 mg (cumulative dose 2,043 mg) of peanut protein without developing dose-limiting allergic symptoms in a double-blind, placebo-controlled food challenge after 9 months of treatment. Other endpoints included safety (i.e. frequency and severity of adverse events) and changes in quality of life related to food allergy, assessed using age-appropriate food allergy quality of life questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM).

Between June 2017 and February 2018, 227 patients were studied, of whom 175 were randomly assigned to the AR101 group (n=132) or the placebo group (n=43). All primary and secondary endpoints were met. 77 (58 %) of 132 participants in the AR101 group tolerated 1,000 mg of peanut protein at the end of the food challenge compared to one (2 %) of 43 participants in the placebo group. Adverse events were reported by almost all participants. The maximum severity of reported adverse events was mild or moderate in most participants who received AR101 (mild, 66 of 132 participants; moderate 63 and severe 1). For placebo, out of 43 participants: mild 24, moderate 18 and severe 0. Participants aged 8-12 years in the AR101 group reported improvements that exceeded the minimal clinically meaningful difference between the two groups in all FAQLQ domains.

Oral immunotherapy with AR101 resulted in rapid desensitisation to peanut proteins, with a predictable safety profile that improved with treatment, and an associated improvement in self-reported and caregiver-reported quality of life related to food allergy.

Jonathan O'B Houhhane et al.: Lancet Child Adolesc Health, 2020 - DOI: 10.1016/52852-4642(20)80284-0

Effectiveness of low-dose OIT

A multicentre, double-blind, randomised and placebo-controlled study investigated the efficacy, safety, immunological parameters, quality of life and treatment burden of low-dose oral peanut immunotherapy (OIT).

62 children in seven German clinics aged 3-17 years with IgE-mecliatecl, confirmed peanut allergy were randomised (1:1) to receive either peanut OIT with a maintenance dose of 125-250 mg peanut protein or placebo. The primary outcome was the proportion ofchildren who tolerated > 300 mg peanut protein in the oral food challenge (OFC) after 16 months of OIT. The occurrence of adverse events (AEs), immunological changes, quality of life (QoL) before and after OIT and burden of treatment (BoT) during OIT were measured.

23/31 (74.2 %) children in the test group tolerated at least 300 mg of peanut groundnut protein at the final OFC, compared with 5/31 (16.1%) in the placebo group (p<.001). 13/31 (41.9 %) of the children in the active group versus 1/31 (3.2 %) of the placebo group tolerated the highest dose of 4.5 g peanut protein at the last OFC (pc.OOl). The peanut OIT group showed a significant reduction in peanut-specific IL-4, IL-5,1 LIO and IL-2 blood mononuclear cell (PBMC) production compared to the placebo group, as well as a significant increase in peanut-specific lgG4 levels and a significant improvement in quality of life. 86% of the children rated the BoT positively.

The study confirmed that low-dose oral immunotherapy is effective in peanut-allergic children, has an excellent safety profile, helps improve quality of life with a low treatment burden, and causes immunological changes that lead to tolerance development.

Blủmchen K et al.: The Journal of Allergy and Clinical Immunology: In Practice. 2019 - DOI: 10.1016/j.jaip.2018.10.048 

Psychosocial effects of peanut allergy

Peanut allergy (PA) is a potentially life-threatening and typically lifelong condition with a significant disease burden. However, there is a lack of information on how affected people and their carers perceive the psychosocial impact.
The Allergy to Peanuts impacting Emotions And Life 1 (APPEAL-1) survey, conducted across Europe, explored the experiences and psychosocial impact of living with PA.

The Allergy to Peanuts impacting Emotions And Life study 1 (APPEAL-1) was an online survey in eight European countries. Representatives from eight patient advocacy groups and five health research specialists developed the survey. Eligible groups included: adults diagnosed with PA (self-report); parents/other caregivers (proxy report for a child with PA); and parents/other caregivers (self-assessment of the impact of PA on themselves).
Of the total 1,846 respondents in the study, 419 were adults with PA (self-report); 546 were parents/carers (proxy report) and 881 were parents/ carers (self-report).

Most respondents reported lifestyle restrictions on food (84 %-93 %), as well as additional areas such as parties and socialising, holiday activities and destinations, and use of public transport (53 %-89 %). About 40 % rated themselves as "very" frustrated and "very" stressed. Two thirds (65 %) felt socially isolated; 43 % were bullied.

Less than half felt safe when it came to using an adrenaline auto-injector.

Several country-specific differences were found, e.g. the highest anxiety scores among respondents from Germany.
Peanut allergy has negative psychosocial effects on patients, leading to frustration, stress and isolation.. Greater attention to these consequences of PA in research and clinical practice is needed.

DunnGalvin A ef al.: Allergy. 2020 - DOI: 10.11U/all.l4S6S

Exposure of children and adolescents with peanut allergies 

The APPEAL-1 study was followed by APPEAL-2, a qualitative study that particularly investigated the stress and coping with peanut allergy in children and adolescents and their caregivers.

Following the recent cross-national European questionnaire survey APPEAL-1, APPEAL-2 assessed peanut allergy (PA) exposure and associated coping strategies through semi-structured interviews.

The objective was to gain qualitative insights into the strategies for coping and managing PA and the impact of these strategies on the quality of life of children, young people and the caregivers.

The qualitative cross-sectional study was conducted in eight European countries: Great Britain, France, Germany, Ireland, Spain, Italy, Denmark and the Netherlands. Semi-structured interviews were conducted with children (8 to 12 years) and adolescents (13 to 17years), with - self-reported - moderate or severe PA and with parents/carers of children and adolescents (aged 4-17 years) with moderate or severe PA. Two conceptual models were developed to illustrate the impact of PA and coping strategies, (a) by individuals with PA and (b) by parentsand carers of children with PA.

107 participants were interviewed, of whom 24 were children, 39 young people and 44 caregivers.
The conceptual models illustrated issues related to coping and control that exist through fear of PA responses and the associated emotional, social, relational impacts and of such on work. Factors moderating these effects include social attitudes and appropriate support, the relationship between child and caregiver, and the coping strategies used.

Conclusion: The APPEAL 2 results support the findings from the APPEAL 1 survey. The results also suggest that the severity of the PA experience does not correlate with the perception of overall exposure and that the impact varies by country, as already shown in APPEAL-1.

DunnGalvinA etal.: Clin Exp Allergy 2020 - DOI: 10.1111/cea.lS719 

"Food allergies require special attention - and new solutions"

Cow's milk allergy is commonly the most common food allergy in early childhood. But increasingly, the peanut is also causing problems?

Yes, a relevant increase in cases can already be observed among young children and adolescents. In Germany alone, the number of cases of peanut allergies is expected to have increased significantly in recent years.

Peanut allergies have long been considered an "Anglo-Saxon" condition, i.e. in Great Britain, the USA or Australia? Is there an explanation why the cases are now also increasing so strongly in Central Europe?

The reason is probably multifactorial. At one point, globalisation has certainly long since reached the domestic plate, and eating habits are becoming more and more similar Peanuts are no longer just a snack you can do without. The well-known warning "may contain traces of peanut’ is found on many packages, sometimes in a surprising context. In addition, there is the growing consumption of ready meals and fast food products even in infancy, which can generally be triggers of food allergies. On the other hand, there are many allergy-promoting substances in the environment, and both pea-nuts and tree nuts cause severe reactions.

But there is also positive news from allergy research, isn't there? Surely significant progress has been made recently?

First of all, the large British LEAP study (Learning Early About Peanut Allergy) from 2015 should be mentioned here. It famously investigated whether an early introduction of peanut into the diet of young children was a way to reduce the risk of such a reaction. The result - a significantly lower number of allergies with early exposure to peanut - surprised experts and sufferers alike. Until then, the only prevention option was strict avoidance. Apparently, however, early contact with low doses of the allergen promotes the development of tolerance, which has a positive effect. In the meantime, these results have also been confirmed in other studies. At the moment, it is still being discussed how to deal with these data in concrete terms, but one thing is clear - the LEAP study has led to a fundamental rethink in the prevention and treatment of peanut allergies and thus opened the door to new therapeutic approaches.

This is somewhat reminiscent of the famous GINI study, which showed that even a certain, only partially hydrolysed infant food can offer similar protection to an extensively hydrolysed food in non-breastfed high-risk infants. And as the 20-year results now showed, even in the long term.

Exactly. Tolerance instead of parental leave is the goal. Early and continuous administration of peanuts in families where peanuts are regularly consumed is now being discussed as a promising option for prevention when there is a risk of peanut allergy. However, oral immunotherapy requires a careful approach, good patient selection and education; peanut contact should be increased slowly and gradually, well observed. However, recent studies show very favourable results for this method.

"Tolerance instead of parental leave is the goal."

Now a drug has been approved that makes oral immunotherapy easier and also safer. Is that so difficult?

The peanut ingredient must have consistent consistency, because a deviation in composition could have fatal consequences. Of course, this must also be secured over a longer period of time and without special storage measures. The current preparation has been tested many times and the study results are very promising.

While there is no cure yet, and the goal is not to be able to eat peanuts indefinitely after therapy, there is still the prospect of reliable protection against accidental contact. Apparently, the peanut allergen is not only effective orally, but also percutaneously, i.e. through accidental skin contact.

This can actually be quite dangerous for the people concerned, can't it?

Peanut allergy carries a risk of anaphylactic shock, which can be life-threatening. In fact, emergency admissions for anaphylaxis have increased significantly in recent years. Fortunately, there have only been very isolated deaths among children. Research has shown that around 60 per cent of children come into unintentional contact with peanuts over a period of five years. Peanut allergy sufferers should therefore always have an emergency adrenaline pen to hand. Furthermore, additional training in its use is still necessary. Because in the panic of an emergency, many affected people, especially children, cannot cope with it or are afraid to use it. More education of the environment is also necessary here.

That sounds quite complicated. So living with a peanut allergy is downright stressful?

Indeed. It should not be forgotten that a peanut allergy is usually persistent, i.e. it persists into adulthood - unlike a cow's milk allergy, for example, where there is a good chance that it will subside in childhood.

Two studies, APPEAL-1 and APPEAL-2, have currently looked at the psychological burden of those affected, as many suffer from a lack of understanding of their disease by those around them. The studies were conducted in eight European countries and there are interesting national differences in the perception and type of impairment of quality of life with "peanut" allergy. APPEAL-2 is dedicated to the specific mental health problems of affected children and adolescents. These results should also give pause for thought and should be increasingly included in future consultations. 

How are children with suspected CMA treated? 

The Cow's Milk Related Symptom Score (CoMiSS®) was developed by leading CMA experts as a sensitisation tool for non-lgE mediated CMA. It supports the diagnostic process by assessing the most common symptoms of CMA, such as crying, gastrointestinal, dermatological and respiratory manifestations.

A multicentre, prospective, observational cohort study investigated the different approaches of different health care disciplines to the diagnosis and treatment of infants with suspected CMA in four European countries. Infants (0-18 months) with suspected mild to moderate CLMA were enrolled by physicians (HCP) in Belgium, the Czech Republic, Germany and the United Kingdom. Age, sex, anthropometric data, the type of diet prescribed for the treatment of CMA and the diagnostic tests performed were recorded. The practitioners ranged from primary care doctors to allergists in a specialist centre, depending on the country.

The doctor conducted two visits at an average of three weeks apart (before and after the CMA elimination diet) using the CoMISS* tool to assess symptoms. Each study centre also completed a questionnaire on satisfaction with CoMISS®.

•    The intention-to-treat (ITT) group (268 infants) was used as the basis for the overall analysis of the results presented, as there was no clinically meaningful difference between the ITT and per protocol groups (208 infants).
•    The nutritional management prescribed varied by site and included breastfeeding, partially hydrolysed formula (pHF), extensively hydrolysed formula (eHF) and amino acid-based formula (AAF).
•    At the first visit, the average CoMISS* score was 11 and decreased statistically significantly to an average of 4 after the elimination diet, underlining the effectiveness of the nutritional intervention. The change in CoMISS value was greater after AAF than after eHF.
•    Large differences between countries were found in the specific diagnostic tests (open oral food provocation, skin prick test and specific IgE blood test) and the actual percentage of tests.
•    Overall, the HCPs involved were very satisfied with the use of CoMISS* in primary care.

The CoMISS perception tool proved to be effective and supportive in the process of diagnosing CMA. The study also found that the diagnosis and treatment of CLWM varies widely across countries, partly due to differences in health system practices.

Vandenplas Y et al.: Nutrients 2021 –

Taste is the deciding factor 

Extensively hydrolysed and amino acid-based special diets are used for the nutritional therapy of non-breastfed children with cow's milk allergy (CMA): The attitudes of health care professionals (HCPs) and caregivers towards the effects of the taste of eHF and AAF on food choice, acceptance and long-term adherence to the diet were investigated.

Disinclination or refusal to eat was attributed to the bad taste of these formulas. 50 HCPs caring for infants with CMA and 300 caregivers of children aged 0-36 months from two cities in France participated. The 50 HCPsand three groups of 100 caregivers (n=150 participants per group) conducted blinded, randomised taste preference trials comparing different eHFs to each other and different AAFs.

In addition, all participants (n= 350) were asked to give their opinion on the importance of taste for infant formula choice, acceptance by the infant, long-term adherence to the diet and cost-effectiveness.
In the taste comparison groups, on average 98 (65 %) participants preferred the taste of the HMO supplemented W-eHF over two of the C-eHF. Parity was mainly achieved in the 3rd eHF peer group.

103 (68.5%) participants preferred the taste of the AAF with HMO over two AAF Parity was reported in the third AAF comparison group.

HCPs and caregivers consider taste to be a critical factor in the selection, acceptance and retention of eHF or AAF for the treatment of infants with CMA. The participants also suggest that better taste could reduce the waste of infant formula and thus have a positive impacton health care costs.

Muraro A ef al.: EAACI Hybrid Congress 2021

CoMiSS facilitates CMA diagnosis

The protein in cow's milk triggers a cow's milk allergy (CMA) in about 2-5 percent of all infants. However, recognition and diagnosis are often inaccurate or delayed, because the symptoms are non-specific and can easily be assigned to other diseases.

The diagnosis of cow's milk allergy (CMA) can be difficult and lengthy, further complicated by the fact that there are IgE and non-lgE mediated types of CMA that cause either immediate or delayed symptoms. The Cow's Milk-related Symptom Score (CoMISS), developed by international experts, is intended to improve the perception of a CMA.

Screening with CoMISS can help to detect early CMA in children < 2 years.

CoMISS can also be used to evaluate and quantify the development of symptoms during therapeutic interventions, but does not replace diagnosis and a food exposure test.

Free download of the CoMiSS symptom score at: nahrungsmittelallergien/comiss 

Guideline: management of IgE-mediated food allergies 

The 2015 guideline was updated after literature searches in PubMed, meta-analyses, clinical trialsand other scientific studies. It takes into account the methodological guidelines of the Association of the Scientific Medical Societies (AWMF) for the development of guidelines for diagnostics and therapy and corresponds to an S2k guideline according to the three- stage concept of the AWMF.

Key statements

•    Primary IgE-mediated food allergies are most likely to result from gastrointestinal sensitisation to predominantly stable food allergens (glycoproteins/lipoproteins).
A secondary IgE-mediated food allergy develops as a result of sensitisation to aeroallergens (e.g. pollen allergens) with subsequent reactions (cross-allergies) to structurally related, often unstable allergens in (plant) foods.
•    The prevalence of food allergies varies regionally and has increased in some countries in recent years, and is generally higher in children than in adults. Geographically, the prevalence in children is highest in north-western Europe compared to adults.
•    The most common food allergy triggers in children and adolescents are milk and chicken egg whites, soy, wheat, peanut and tree nuts.
•    Data on the course of food allergy show that early childhood cow's milk allergy has a good prognosis in terms of spontaneous tolerance development, while peanut and tree nut allergies are more likely to persist into adulthood.
•    A detailed anamnesis should be the basis for the diagnosis of food allergy.
•    Specific IgE determination and skin prick test support the diagnosis of food allergy in the context of history and/or food provocation.
•    Non-breastfed infants with suspected cow's milk allergy require a cow's milk substitute for the period of diagnostic elimination in the form of an extensively hydrolysed infant formula or an amino acid formula, which should be selected individually.
•    Oral food challenge (especially double-blind placebo-controlled) is the gold standard in the diagnosis of IgE-mediated food allergies.
For safety reasons, oral provocations should only take place where allergic reactions, including anaphylaxis, can be treated adequately and age-appropriately. Staff should be trained and experienced in early detection and emergency management.
•    In the case of cow's milk allergy, which already occurs in the first year of life, a special therapeutic food (extensive hydrolysate, amino acid formulas) is required. Which specific food is chosen has to be decided individually: As a rule, extensive hydrolysate is the first choice. For sufferers with severe symptoms (especially gastrointestinal), amino acid formulas can be beneficial.
•    Soy foods cannot be recommended for infants under 12 months of age.
•    Asa rule, partially hydrolysed infant formulae arejust as unsuitable as sheep's or goat's milk for the therapy of cow's milk allergy [163,164], If a partially hydrolysed infant formula is tolerated [150], it can be retained.
•    The use of probiotics and prebiotics cannot be recommended for the therapy of food allergy at present due to insufficient data.
•    In children between 4 and 17 years of age with a confirmed diagnosis of systemic peanut allergy, oral immunotherapy with an approved preparation should be offered, taking into account an individual benefit-risk assessment.

Worm M et air Allergologieselect. 2021 - DOI 10.5414/ALX02257

Milk oligosaccharides and allergies

What influences the development of a healthy gut microbiome and what are the effects of human milk oligosaccharides (HMO)? What role do they play in children with a cow's milk allergy? An up-to-date overview.
The determinants of early microbiome development in infants were investigated in the TEDDY study, which analysed 12,500 consecutive stool samples from 903 infants between birth and 26 months. Several nutritional and environmental factors were identified, but breast milk had the most prominent influence in the first years of life.

The oligosaccharide 2'fucosyl-lactose (2 FL) found in breast milk promotes healthy bacteria such as bifidobacteria and reduces the growth of pathogenic strains such as streptococci, as shown in a study on the relative abundance in infants of sSecretor-positive versus Secretor- negative mothers. Overall, human milk oligosaccharides (HMOs) have a number of effects that support the immune system of infants and young children with CMA.

A study in healthy infants fed cow's milk-based infant formula supplemented with 2'FL and lacto-N-notetraose (LNnT) showed that the composition of the faecal microbiome of infants fed the HMO-supplemented formula was significantly different from that in the control formula group and approached that of breastfed infants. This is especially true for the abundance of bifidobacteria.

The multicentre CINNAMON study investigated infant growth, tolerability and safety of an extensively hydrolysed whey-based infant formula (W-eHF) with 2'FL and LNnT in infants with CMA. A practically identical control diet without HMO served as a comparison. The pro-protocol group for microbiome analysis included 132 infants (68 control/64 HMO infants - the sex ratio was similar). The HMO group was slightly younger than the control group (mean age at admission 98.6 days and 107.9 days, respectively). Stool samples were collected at four time points during the CINNAMON study: at baseline (Visit [V] 0, with infants aged between 14 days and 6 months at baseline), at 1 and 3 months (V1/V3) and at 12 months (V6).

Data from the CINNAMON stool microbial diversity development study showed that the gut microbiome of infants receiving an HMO- supplemented test diet had lower diversity at 12 months of age (V6). The effect of HMO supplementation on the abundance of certain bacterial species was investigated in VI. Grouped by genus, there was a significant enrichment of Bifidobacterium species, with these key bacteria being more abundant in HMO-treated infants.

A post-hoc sub-analysis was also conducted in infants aged < 3 months at time VO (i.e. before the start of complementary feeding, an important factor influencing bacterial composition) to determine whether the change in bifidobacterial abundance between VO and VI was influenced by the type of supply. These results showed that the positive effect of HMO supplementation on bifidobacteria was greatest in infants born by caesarean section.

Fecal community types (FCT) within the gut microbiome have been shown to evolve with age during the first year of life in both study groups of the CINNAMON study, reflecting changes in diet and environmental exposure. In infants fed either HMO-supplemented or control diets, transition models using all 481 study samples showed a temporal evolution from "early" to "late" FCT clusters, reflecting a gradual shift to an "older" microbiome.

The positive effect of HMO supplementation on the age of the microbiome was confirmed by comparing the differences in FCT distribution between treatment groups stratified by visit between baseline and V6 (figure).

Overall, the results show that HMOs play a central role in shaping the developing gut microbiome of infants with CMA. Supplementation with 2'FL and LNnT in both the standard and a W-eHFdiet is associated with an enrichment of bifidobacteria and lower microbial diversity, as well as a lower age of the gut microbiota at 12 months of age.

Heine R: EMJ Allergy and Immunology, 2021 

In vitro study shows: HMOs can reduce type 2 immune responses 

Human milk oligosaccharides (HMOs) appear to be able to influence the immune response and the function of the intestinal barrier through direct cellular interaction as well as indirectly through their prebiotic effect on the composition and function of the gut microbiome. A new in vitro study investigated the influence of a combination of two HMOs on type 2 immune response and gut barrier function.

A mixture of 2'-fucosyIlactose (2'FL) and lacto-N-neotetraose (LNnT) in a ratio of 2:1 was used. A comparison was made with the effect of lactose and mixtures of widely used pre- biotics (inulin; fructo-oligosaccharides = FOS; galacto-oligosaccharides = GOS; cow's milk oligosaccharides = BMOS).

A rat basophil cell line (RBL) and deviant type 2 peripheral blood mononuclear cells (PBMC) were used to test the effect of these ingredients on RBL degranulation and type 2 cytokine levels [interleukin (IL)-5 and IL-10], In addition, the ability of the HMO mixture to modulate intestinal epithelial barrier dysfunction triggered by inflammatory cytokines was tested.

The 2'FL-LNnT combination significantly reduced RBL degranulation. GOS, BMOSand lactose showed a similar effect, while the results with inulin, FOS or a combination of inulin and FOS were not significant. A multilevel analysis of variance showed that the addition of 2'FL-LNnT to the HMO mixture was associated with lower RBL degranulation. The 2'FL-LNnT mixture significantly decreased IL-5 production in the Th2-heavy PBMC assay, with no significant differences from FOS, GOS, lactose, inulin or with combinations of FOS-GOS or FOS-inulin. In the PBMC assay, no effect of any of the substances used on IL-10 modulation was observed. Finally, we found that the 2'FL-LNnT mixture significantly improved the barrier function of the intestinal epithelium.

A 2'FL-LNnT mixture is better at attenuating type 2 reactions while increasing gut barrier function compared to widely used prebiotic ingredients.

Chung CKW et al.: EAACI Hybrid Congress 2021

Safety and suitability of an amino acid-based diet (AAF) with HMO

Does an amino acid formula (AAF) supplemented with two human milk oligosaccharides (HMO) support normal growth and is it well tolerated by infants with moderate to severe cow's milk allergy (CMA)?

To this end, an open-label, non-randomised, multicentre, single-intervention study was conducted at six paediatric facilities in Australia. Included were infants aged 1-8 months with moderate to severe CMA who had failed a trial of extensively hydrolysed formula (eHF) or rice-based formula (RBF) and reguired AAF as first-line treatment. The study diet was an AAF supplemented with two HMDs, 2'fucosyl-lactose (2'FL) and lacto-N-neotetraose (LNnT). The infants were fed the diet for 4 months (V0-V4) and continued to be fed as needed for up to 12 months. From the age of 4-6 months, the infants were given a cow's milk protein-free complementary diet.

Z-scores for weight for age (WAZ), length for age (HAZ) and head circumference for age (HCAZ) were calculated based on WHO growth percentiles. Tolerability and safety were assessed by adverse events (AEs) reported during the study.

Of 34 infants studied, 32 were enrolled in the study and 29 completed the study by V4. The mean age at VO was 18.6 + 8.0 weeks, 20 were male.

During the main study period (VO to V4), the mean GTE increased from -0.31 to +0.28. Similarly, the mean HAZ increased from +0.26 to +0.60 and the mean HCAZ from +0.63 to +0.91.

A total of 232 AEs occurred, of which 192 (82.8%) were classified as mild, 37 (15.9 %) as moderate and 3 (1.3 %) as severe. All moderate or severe AEs were classified as unrelated to the study formula or unlikely to occur. In 2 (6.3 %) infants, the preparation was discontinued due to mild side effects (gastrooe- sophageal reflux [n=l], liguid stools, flatulence and reduced food intake [n =1]).

Infants with moderate to severe CMA fed the study diet with two HMOs achieved normal growth with some catch-up growth. Apart from a small number of non-serious gastrointestinal side effects, the diet was well tolerated and had an excellent safety profile.

Gold MS etal: EAA Cl Hybrid Congress, July 2021 

Starting complementary food and allergies

What is the relationship between the timing of introduction of complementary foods or the type and amount of complementary foods consumed and the development of food allergies, atopic dermatitis/eczema, asthma and allergic rhinitis? 

The aim of this study was to answer this question using systematic reviews conducted for the USDA (United States Department of Agriculture) and the Pregnancy and Birth to 24 Months Project of the US Department of Health and Human Services.

The literature was searched using four databases for articles published between January 1980 and February 2017 that met the inclusion criteria.

For each study, the data were extracted and the risk of bias was assessed. The evidence was obtained qualitatively and the strength of the evidence was graded. 31 included articles dealt with the timing of introduction of complementary feeding and 47 articles with the type and amount of complementary feeding consumed.

The key results:

•    Limited to strong evidence, depending on the specific food, suggests that introducing allergenic foods in the first year of life (after 4 months) does not increase the risk of food allergies and atopic dermatitis/eczema, but may prevent peanut and chicken egg allergies.
•    There is insufficient evidence of a link between dietary diversity or dietary patterns and atopic diseases.

 More research is needed to address gaps and limitations in the evidence on the development of atopic diseases, including research that uses valid a nd reliable diagnostic criteria and takes into account important confounding factors and possible reverse causality.

ObbagyJE et al.: Am J Clin Nuti: 2019 - DOI: 10.109S/ajcn/nqy220

Early introduction of food allergens

There is increasing evidence that early introduction of allergenic foods can reduce the risk of developing IgE-mediated food allergy. Food introduction guidelines prior to the publication of the LEAP (Learning Early about Peanut Allergy - 2015) study are not well studied, but are important for assessing subsequent changes in infant feeding practices and the association with potential food allergies.

A retrospective longitudinal study examined data from a multicentre cohort of infants hospitalised with bronchiolitis between 2011 and 2014. The primary endpoints were IgE-mediated chicken egg or peanut allergy at 3 years of age. Of 770 participants included in the analysis, 635 (82 %) had a chicken egg allergy and 211 (27 %) had a peanut allergy at 12 months of age, according to their parents. Four participants had a probable chicken egg allergy and eight participants had a probable peanut allergy at the age of 3 years. Regular egg consumption in infancy was associated with lower chicken egg allergy. Peanut allergy cases did not occur with peanut consumption in infancy. Overall, the results indicate that the early introduction of groundnut was unusual before 2015. Although limited by the low number of allergies, the data suggest that early introduction of egg and peanut is associated with a lower risk of developing food allergy. They thus support the recent changes to the practice guidelines.

Yakaboski E et al.: Nutrients. 2021 –

Obesity and food allergies 

Food allergies are a common condition in children and their prevalence has increased in developed countries. At the same time, the impact of obesity on children's health is becoming a problem. However, a connection between the two strains is still unclear.

A recent study investigated the relationship between obesity and the prevalence of food allergies in Japanese children. Data from 1,772 Japanese children (878 males) who were interviewed with a questionnaire were analysed. Using the BMI cut-off values proposed by the International Obesity Task Force, two groups were formed: overweight and not overweight. The children were divided into four age groups (3-6 years, 6-9 years, 9-12 years and 12-15 years). Univariate and multivariate logistic models were applied to investigate the association between obesity and food allergies.

The prevalence of obesity was significantly higher in boys (19.9 X/12.9 %), and the difference was not significant for food allergies (7.4 %/6.3 %). In the age groups, a significantly higher prevalence was found in boys (10.6 %) than in girls (4.5 %) at 6-9 years. In contrast, the picture was reversed among 12-15-year-olds (7.9 % for girls/2.5 %for boys). While the prevalence of food allergies in the 12-15 age group was significantly higher in overweight girls than in non-overweight girls (26.17o,p = 0.005), no significant difference was found in boys. In girls, overweight was signifi-cantly associated with food allergies after adjusting for age and asthma.

The results show that obesity is significantly associated with a higher prevalence of food allergies in girls, but not in boys. Further prospective studies are needed to determine the causal relationship between obesity and food allergies.

Hayashi et al. Environmental Health and Preventive Medicine. 2021,26-44 - 

Obesity may contribute to persistent allergic rhinitis in children 

Obesity and overweight are associated with a higher risk of allergic rhinitis (AR) in children. One study investigated the mechanisms by which obesity affects the severity of AR via leptin and interleukin (IL)-1β.

210 children with AR and 82 without AR were included in the study. Leptin and inflammatory biomarkers were measured in serum to investigate correlation with AR severity. Serial follow-up of the obese children was also used to analyse whether changes in BMl regulate the severity of AR.

IL-1lβ, a biomarker of active inflammation in AR, was significantly higher in the children with AR than in those without AR and higher in subjects in the obesity group than in those in the normal weight group. Regression analysis showed that leptin levels were associated with increased IL-1β expression in children with AR. In multivariate analysis, only parental AR (9.2-fold increase in risk), elevated leptin levels (11.3-fold increase in risk) and high expression of IL-1β (5.8-fold increase in risk) were found to be significant risk factors for moder- ate-to-severe persistent allergic rhinitis.

With an increase or decrease in BMI, the children showed changes in IL-1β and AR symptoms, these changes were dependent on leptin and BMI. These findings suggest that obesity is an important risk factor for worsening symptoms and that leptin may exacerbate inflammation and severe and persistent symptoms through IL-1β in AR.

Han MW et al.: Int Arch Allergy Immunol 2021;182:546–552 – DOI:10.1159/000512920

Obesity and asthma 

Obesity increases the prevalence of asthma and is associated with poorer treatment outcomes. The treatment of this patient group poses special challenges for research and the clinic.

Recent studies have confirmed a bidirectional relationship between obesity and asthma. Pathophysiological factors involved include genetic risk, the effects of diet and microbiome, and obesity-related cytokines.

The aim is to phenotype this group of patients with different clinical presentations based on age of onset of asthma. However, the inadequacy of biomarkers and conventional pulmonary function tests complicates the diagnosis, phenotyping and treatment of obese asthma patients. Furthermore, there is a lack of targeted intervention options, although weight loss obviously has some benefits.

Mohan A, Grace J, Wang BR et al.: Curr Allergy Asthma Rep 19, 49 (2019).

Entry into the "allergic march"? 

Cow's milk allergy (CMA) in early childhood could be one of the first stages of the "allergic march" leading to the later onset of other atopic manifestations, including asthma and ocular inflammation.

In recent years, nutrition has emerged as a relevant strategy for the prevention of allergic diseases, based at least in part on epigenetic modulation of the immune system. Although CMA naturally resolves over time in most affected individuals, studies in recent decades demonstrate a wide range of ages and rates of resolution with an increased risk of persistence. This is mainly due to a negative gene-environment interaction leading to the breakdown of immune tolerance mechanisms.

In addition, there is evidence that CMA in early childhood is one of the first stages of the "allergic march" that leads to the onset of other allergic diseases later in life. Indeed, the occurrence of allergic sensitisation in these children increases the risk of later developing asthma and allergic oculorhinitis/AR, especially if the sensitisation occurs together with atopic dermatitis (AD). Several clinical studies show that up to 45% of CMA children develop further atopic manifestations later in life - even after immune tolerance to cow's milk proteins has been achieved.

The development of allergic march is driven by a genetic predisposition, but environmental factors can also play an important role in the clinical expression. As shown in longitudinal studies, only a minority of children follow the classical path of the allergic march (starting from AD and successively developing food allergy, asthma and AR).
Early identification of children at risk, regardless of the timing of the onset of CMA, allows effective strategies to limit the subsequent onset of other atopic manifestations.

Vitamin D for the prevention of childhood food allergies 

The role of vitamin D beyond bone and calcium metabolism is not yet fully understood. Its importance for the prevention of food allergies has also been studied many times, but with contradictory results.

The effect of vitamin D in calcium and bone physiology is well known, but calcitriol, the active form of vitamin D, also influences epithelial cells, T cells, B cells, macrophages and dendritic cells. Almost all cells of the adaptive immune system express the vitamin D receptor, so that they can also react to the vitamin. Specific to the potential role of vitamins in food allergy, vitamin D has been shown to influence several mechanisms that promote immune tolerance, including regulatory T cell function and induction of tolerogenic dendritic cells.

However, there is conflicting data on the link between vitamin D deficiency and the development of food allergy in children. Some studies link lower sunlight exposure to food allergies. In contrast, other studies have found that higher vitamin D levels could increase the likelihood of allergic sensitisation and food allergy.
There is an urgent need for well-designed, randomised and controlled trials of vitamin D supplementation, especially with regard to the prevention of food allergies.

•    Vitamin D is a hormone with pleiotropic effects that is important not only for calcium homeostasis and bone mineralisation, but also for the proper functioning of the immune system.
•    However, some patients do not benefit from vitamin D supplementation because they have genetic alterations in metabolism rather than uptake.
•    The link between vitamin D and the develop-ment of food allergies is contradictory.
•    There is a possible link between lower sunlight exposure and food allergies; on the other hand, higher vitamin D levels may increase the likelihood of allergic sensitisation and food allergy.
•    Vitamin D needs to be considered as another opportunity for understanding and treating atopic diseases.
•    There is an urgent need for well-designed, randomised controlled trials of vitamin D supplementation for food allergy.

Giannetti A et al.: Front. Pediatr. 8:447 – DOI:10.3389/fped.2020.00447

Benefits of entera[ nutrition with a mixed diet 

Recently, children in the UK who need tube feeds have been fed more and more with homemade mixed diets. But this increases the risk of tube occlusion and inadequate nutrient supply.

Recently, the British Dietetic Association (BDA) updated its position statement on liquid diets via a gastrostomy tube to encourage a more open discussion with patients and carers about mixed diets.

Now a tube feed has been developed to avoid safety and nutritional shortcomings. A study tested them against the UK Advisory Committee on Borderline Substances (ACBS) criteria for prescribing in the National Health Service (NHS). All participants (n=19; 1-14 years) were tube fed, recruited by the NHS and managed by a dietitian/physician. They were given the new milk formula Isosource Junior Mix (ISJMIX) for 7 days. Demographic and medical data were collected, gastrointestinal tolerance was recorded and stool type was defined using the Bristol stool chart. The participants (1-14 years) suffered from a range of different conditions and symptoms of food intolerances.

Improvements in these symptoms were reported after switching to a special tube feed with ingredients from food sources, resulting in an improved quality of life for the children and their families. Some participants reported improved consistency of stool. One child noted improved mood, eye contact and concentration. Decrease in reflux and gradual decrease in retching were observed in 2 participants. One child suffered from flatulence and bloating; he previously received a tube feed without fibre, which could have caused the symptoms. There were no changes in weight during the study.

The new tube feed was well tolerated by the majority of participants and Gl symptoms decreased. Tube feeding with ingredients from foods could be considered as a sole source of nutrition or in combination with mixed diets if children cannot tolerate a standard diet.

Thornton-Wood C, Saduera S: J Neonatol Clin Pediatr 2020, 7: 050 – DOI: 10.24966/NCP-878X/100050

New studies suggest that the use of blended diets (BD) is increasing in enteral-fed children. Parents report that the mixed diet leads to significant positive changes in the children's physical health and well-being. A study has shown that BD is well tolerated and food intolerance decreases after starting the diet.

In 2019 the British Dietetic Association (BDA) changed its position on BD and now encourages open discussion with dietitians and parents about the potential risks and benefits of BD. Commercially available foods containing food-derived ingredients have been shown to improve food intolerance symptoms.

A recent study investigated the tolerability and acceptability of a 1.2 kcal/ml diet with 14% ingredients from food sources in children aged 1-14 years with a range of medical conditions. There was improved stool consistency and less gagging and retching. This suggests that dietary ingredients can alleviate the symptoms of food intolerances.

Using the example of four children aged between 26 months and 10 years who participated in the study, the improvements are presented. These children have a range of conditions including learning and physical disabilities, digestive tract abnormalities and genetic conditions such as DiGeorge syndrome. Reflux, constipation and vomiting were among the reported symptoms of food intolerance.

Significant improvements in these symptoms were reported after a switch to tube feeding, resulting in improved quality of life for the children and their families.

Conclusion: Tube feeding with ingredients from food sources could be considered as a sole diet or in combination with BD if children cannot tolerate a standard diet.

Siddiqui A et al.: J Neonatol Clin Pediatr 2021, 8: 066 – DOI: 10.24966/ NCP-878X/100066

Healthy or sustainable? 

In the face of environmental degradation, climate change and overpopulation, nutrition is also increasingly in focus. Not only what is healthy, but also what is sustainable consumption?

While the shift to healthier diets has shown great potential to reduce the environmental footprint, current policy initiatives are primarily concerned with strategies to reduce food waste. The ambitious goal is to halve food waste at retail and consumer level by 2030. A recent study by the Faculty of Environment and Natural Resources at the Albert Ludwig University of Freiburg compared the options. Using Germany as an example, the resource-saving potential of this political goal was examined for interactions and trade-offs with three scenarios of nutritionally sensible, plant-based dietary patterns. Using the Food and Agriculture Biomass Input-Output Model, biomass, arable land and blue water footprints of global supply chains were recorded.

The results show that changing dietary habits is particularly effective in reducing the biomass and arable land footprints (up to -61 % and -48 % respectively), while halving food waste reduces them by 11 % and 15 % respectively. For water, halving food waste is more effective: water consumption decreases by 14 %, while it increases by 6 % for the dietary change with the highest water consumption. The combination of scenarios offers the highest overall savings potential.

However, the results also show that dietary change can lead to a greater amount of food waste despite a reduced footprint, as consumption of products with a higher proportion of food waste increases.

The conclusion of the Freiburg research group: higher resource efficiency could be achieved if the reduction potentials of all available strategies are exhausted and their interactions are taken into account at the same time.

Helander H et al.: Environ. Res. Lett. 16 (2021), 054033 –